Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

• the present invention relates to a process for the preparation of letrozole free from its regioisomer and other impurities
• Aromatase is an enzyme, which effects aromatisation of ring A in the metabolic formation of various steroid hormones.
• Various cancers for example, breast cancer is dependent upon circulating steroid hormones, which have an aromatic ring A.
• Such cancers can be treated by removing the source of ring A aromatised steroid hormones, for example by the combination of oophorectomy and adrenalectomy.
• An alternative way of obtaining the same effect is by administering a chemical compound, which inhibits the aromatisation of the steroid ring A.
• Letrozole is a non-steroidal antineoplastic, claimed to inhibit the aromatase (oestrogen synthase) activity. It is useful in the treatment of advanced breast cancer in postmenopausal women.
• estrogens The growth of some cancers of the breast are stimulated or maintained by estrogens.
• Treatment of breast cancer thought to be hormonally responsive i.e., estrogen and/or progesterone receptor positive or receptor unknown
• estrogen levels i.e., adrenalectomy, hypophysectomy
• estrogen effects antiestrogens and progestational agents
• estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol.
• the suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
• Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult tumor bearing females, Letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with Letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.
• Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues.
• Treatment of women with Letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.
• Letrozole is reported in U.S. Pat. No. 4,978,672 and EP 236,940.
• the synthesis of Letrozole starts with 4-bromomethylbenzonitrile (1), which undergoes condensation with 1,2,4-triazole (2) to form 4-[(1,2,4-triazol-1-yl)methyl]benzonitrile (3) as an intermediate.
• the compound of structural formula (3) is purified by column chromatography to remove 4-[(1,3,4-triazol-1-yl)methyl]benzonitrile (4) and followed by reaction with 4-fluorobenzonitrile (5) to afford Letrozole (6).
• the undesired intermediate 4-[(1,3,4-triazol-1-yl)methyl]benzonitrile (4) is formed during the course of the preparation 4-[(1,2,4-triazol-1-yl)methyl]benzonitrile (3) in 10% w/w to 30% w/w.
• Letrozole intermediate (3) which is free from its regioisomer (4) and other related impurities.
• the present invention relates to Letrozole (6) with its regioisomer 4-[1-(4-cyanophenyl)-1-(1,3,4-triazol-1-yl)methyl]benzonitrile (7), preferably, less than 0.3% w/w, more preferably, less than 0.1% w/w and most preferably, below the quantitation limit.
• the present invention provides an improved process for the preparation of Letrozole with its regioisomer 4-[1-(4-cyanophenyl)-1-(1,3,4-triazol-1-yl)methyl]benzonitrile (7), preferably, less than 0.3% w/w, more preferably, less than 0.1% w/w and most preferably, below the quantitation limit.
• the present invention provides 4-[(1,2,4-triazol-1-yl)methyl]benzonitrile (3) with its regioisomer 4-[(1,3,4-triazol-1-yl)methyl]benzonitrile (4), preferably, less than 0.3% w/w, more preferably, less than 0.1% w/w and most preferably, below the quantitation limit.
• the present invention provides an improved process for the preparation of 4-[(1,2,4-triazol-1-yl)methyl]benzonitrile (3) with its regioisomer 4-[(1,3,4-triazol-1-yl)methyl]benzonitrile (4), preferably, less than 0.3% w/w, more preferably, less than 0.1% w/w and most preferably, below the quantitation limit.
• the main aspect of the present invention relates to the preparation of Letrozole (6) with its regioisomer (7) preferably less than 0.3%, more preferably less than 0.1% and most preferably below quantitation limit.
• Another important aspect of the present invention relates to the preparation of 4-[(1,2,4-triazol-1-yl)methyl]benzonitrile (3) in the pure form, free from its regioisomer 4-[(1,3,4-triazol-1-yl)methyl]benzonitrile (4).
• Letrozole intermediate 4-[(1,2,4-triazol-1-yl)methyl]benzonitrile (3) is prepared with its regioisomer 4-[(1,3,4-triazol-1-yl)methyl]benzonitrile (4) less than 30% and followed by the preparation of Letrozole enriched with its regioisomer (7), which is removed by using crystallisation method using suitable solvent system.
• the present invention relates, inter alfa, to an improved process of Letrozole with its regioisomer 4-[1-(4-cyanophenyl)-1-(1,3,4-triazol-1-yl)methyl]benzonitrile (7), preferably less than 0.3% w/w, more preferably less than 0.1% w/w and most preferably below quantitation limit and other impurities as discussed earlier below 0.1% w/w or below quantitation limits, which are arising due to impure intermediate 4-[(1,2,4-triazol-1-yl)methyl]benzonitrile (3) contaminated with regioisomer 4-[(1,3,4-triazol-1-yl)methyl]benzonitrile (4) and quaternary ammonium salt (10).
• the present invention relates to an improved and efficient process for the preparation of Letrozole with its regioisomer 4-[1-(4-cyanophenyl)-1-(1,3,4-triazol-1-yl)methyl]benzonitrile (7), preferably less than 0.3% w/w, more preferably less than 0.1% w/w and most preferably below quantitation limit and other impurities as discussed earlier preferably less than 0.1% w/w and most preferably below quantitation limits.
• the impurities contaminating Letrozole are mainly due to impure intermediate 4-[(1,2,4-triazol-1-yl)methyl]benzonitrile (3) contaminated with regioisomer 4-[(1,3,4-triazol-1-yl)methyl]benzonitrile (4) and quaternary ammonium salt (10).
• intermediate 4-[(1,2,4-triazol-1-yl)methyl]benzonitrile (3) is required to be of the great purity free from its regioisomer (4) and other related impurities.
• the present invention relates to the removal of Letrozole intermediate regioisomer (4) from the reaction mixture.
• the regioisomer is removed by the selective extraction of intermediate (3) from the mixture of its regioisomer (4) using suitable solvents.
• the reaction of p-Cyanobenzylbromide (1) takes place with 1,2,4-Triazole (2) in Isopropanol in the presence of potassium carbonate at 60-65° C.
• the reaction mixture is quenched in water and pH of the reaction mixture is adjusted to acidic by slowly addition of sufficient amount of cone. HCl.
• suitable solvent preferably hydrocarbons to extract desired product (3) selectively in organic layer.
• the aqueous layer is basified to pH 7.5 to 10, preferably 7.5-8.0, saturated with sodium chloride and again extracted using the same organic solvent to extract remaining intermediate (3). All the organic layers on mixing and washing with water remove any contamination of regioisomer (4) from the organic layer. Removal of solvent and crystallization of product from suitable solvent gives 4-[(1,2,4-triazol-1-yl)methyl]benzonitrile (3) in more than 99% purity with regioisomer below detection limits.
• 13C-NMR of the quaternary salt shows peaks at ⁇ 49.99, 54.10, 111.59, 111.73, 118.42, 129.39, 129.81, 130.12, 132.70, 133.27, 137.47, 138.73, 143.62 and 145.19 supporting the impurity as quaternary salt (10).
• the present invention relates to the preparation of Letrozole with quaternary salt preferably less than 0.1% and more preferably below quantitation limit. Formation of quaternary salt is controlled by optimization of the mole ratio of 1,2,4-triazole during the course of reaction. Mole ratio of 1,2,4-triazole is optimized preferably from 1.5 mole to 4.4 mole equivalent and more preferably to 3.0 mole equivalents with respect to 4-bromomethylbenzonitrile (1).
• the present invention relates to process for the preparation of Letrozole (6) with quaternary salt (10) preferably less than 0.1% and more preferably below quantitation limit.
• the reaction of p-Cyanobenzylbromide (1) with 1,2,4-Triazole (2) on completion is extracted in a suitable solvent getting a 4-[(1,2,4-triazol-1-yl)methyl]benzonitrile (3) in crude form as a mixture with its regioisomer 4-[(1,3,4-triazol-1-yl)-methyl]benzonitrile (4) varying from 10% to 30% and other related impurities.
• the present invention also relates to provide an improved process for preparation of Letrozole with impurity 4,4′,4′′-methylidenetrisbenzonitrile (10), preferably less than 0.2% w/w, more, preferably, less than 0.1% w/w and most, preferably, below the quantitation limit.
• the present invention also relates to the process for the preparation of Letrozole (6), with any known or unknown impurity preferably less than 0.1% w/w and more preferably below quantitation limit.
• THF 500 mL
• Potassium tert-butoxide 122 gm
• the solution was cooled to ⁇ 15° C. and a solution of 4-[(1,2,4-triazol-1-yl)methyl]benzonitrile (100 g), and p-fluorobenzonitrile (86 g) in THF (500 mL) was added very slowly to the reaction mixture in 4-5 hrs.
• the reaction mixture was stirred at same temperature for 3 hrs. Progress of the reaction was monitored on TLC.
• Reaction mixture is added to another flask containing water (220 ml). pH of the reaction mixture is adjusted to 7-8 by addition of 5% sodium bicarbonate solution (180 mL). Dichloromethane layer is washed with water (200 mL), separated, filtered through hyflow bed and distilled at a temperature below 50° C. The residue obtained was crystallized from Isopropanol (20 mL) to get the solid product (4.9 g). HPLC Purity: 89.6%. Regioisomer: 7.41%.
• the Letrozole may be prepared with the desired limit of its regioisomer (7).

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Extraction Or Liquid Replacement (AREA)

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• 2006
  • 2006-09-04 EP EP06842739A patent/EP1945618A2/fr not_active Withdrawn
  • 2006-09-04 US US12/083,665 patent/US20100190997A1/en not_active Abandoned
  • 2006-09-04 WO PCT/IN2006/000337 patent/WO2007054964A2/fr active Application Filing

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